Omega-3 Fatty Acids Upregulate SIRT1/3, Activate PGC-1α via Deacetylation, and Induce Nrf1 Production in 5/6 Nephrectomy Rat Model

Abstract

Mitochondrial dysfunction contributes to the pathogenesis of kidney injury related with cardiovascular disease. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) protects renal tubular cells by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2). AMP-activated protein kinase (pAMPK)-mediated phosphorylation and sirtuin 1/3 (SIRT1/3)-mediated deacetylation are required for PGC-1α activation. In the present study, we aimed to investigate whether omega-3 fatty acids (FAs) regulate the expression of mediators of mitochondrial biogenesis in 5/6 nephrectomy (Nx) rats. Male Sprague-Dawley rats were assigned to the following groups: sham control, Nx, and Nx treated with omega-3 FA. The expression of PGC-1α, phosphorylated PGC-1α (pPGC-1α), acetylated PGC-1α, and factors related to mitochondrial biogenesis was examined through Western blot analysis. Compared to the control group, the expression of PGC-1α, pAMPK, SIRT1/3, Nrf1, mTOR, and Nrf2 was significantly downregulated, and that of Keap 1, acetylated PGC-1α, and FoxO1/3, was significantly upregulated in the Nx group. These changes in protein expression were rescued in the omega-3 FA group. However, the expression of pPGC-1α was similar among the three groups. Omega-3 FAs may involve mitochondrial biogenesis by upregulating Nrf1 and Nrf2. This protective mechanism might be attributed to the increased expression and deacetylation of PGC-1α, which was triggered by SIRT1/3.

Keywords: nuclear factor erythroid 2-related factor 2; nuclear respiratory factor 1; omega-3 fatty acid; peroxisome proliferator-activated receptor gamma coactivator-1 alpha; sirtuin 1; sirtuin 3.

Figure 1

Expressions of (A) Nrf1 and (B) Nrf2 (n = 6/group). Decreased Nrf 1 and Nrf2 expressions of 5/6 nephrectomy group were improved by omega-3 FA supplementation. * p value < 0.05 (mean values are significantly different from control). ^a p value < 0.05 (mean values are significantly different from the Nx group).

Figure 2

Changes in the (A) expression of PGC-1α and (B) activity of PGC-1α (n = 6/group). Decreased PGC-1α expressions of 5/6 nephrectomy group were improved by omega-3 FA supplementation. The deacetylation status of PGC-1α was improved by omega-3 FA supplementation. p-PGC-1α, phosphorylated PGC-1α. PGC-1α-Ac, acetylated PGC-1α. * p value < 0.05 (mean values are significantly different from control). ^a p value < 0.05 (mean values are significantly different from the Nx group).

Figure 3

Changes in the expression of factors related to the function of PGC-1α (n = 6/group): (A) phosphorylation of AMPK (the ratio of pAMPK to AMPK), (B) expression of SIRT1, and (C) SIRT3. Decreased SIRT3 expressions of 5/6 nephrectomy group were improved by omega-3 FA supplementation. * p value < 0.05 (mean values are significantly different from control). ^a p value < 0.05 (mean values are significantly different from the Nx group).

Figure 4

Changes in the expression of mTOR and Keap1 (A–C, n = 6/group). Changes in the expression of FoxO1 and FoxO3 (D–F, n = 6/group). Decreased mTOR and increased Keap1, FoxO1, and FoxO3 expressions of 5/6 nephrectomy group were improved by omega-3 FA supplementation. * p value < 0.05 (mean values are significantly different from control). ^a p value < 0.05 (mean values are significantly different from the Nx group).

Figure 5

Effect of omega-3 FA on mitochondrial biogenesis in CKD. Bold black arrows indicate the expression of mediators related to mitochondrial biogenesis in a CKD rat model. Red arrows indicate the expression of mediators after omega-3 FA administration. Up/down arrows indicate an increase and decrease in the expression of mediators.